WO2016025640A1 - Composés hétéroaryle et utilisations associées - Google Patents

Composés hétéroaryle et utilisations associées Download PDF

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WO2016025640A1
WO2016025640A1 PCT/US2015/044918 US2015044918W WO2016025640A1 WO 2016025640 A1 WO2016025640 A1 WO 2016025640A1 US 2015044918 W US2015044918 W US 2015044918W WO 2016025640 A1 WO2016025640 A1 WO 2016025640A1
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compound
formula
oglu
present
cancer
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PCT/US2015/044918
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English (en)
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Upendra Purush DAHAL
Matthew T. LABENSKI
Lixin Qiao
Sekhar S. Surapaneni
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Celgene Avilomics Research, Inc.
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Publication of WO2016025640A1 publication Critical patent/WO2016025640A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention provides various forms and compositions useful as inhibitors of ER kinases, for example one or both of ERKl and ERK2 kinases.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
  • the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras.
  • Activation of Ras leads to the recruitment and activation of Raf, a serine- threonine kinase.
  • Raf Activated Raf then phosphorylates and activates MEKl/2, which then phosphorylates and activates one or both of ERKl and ERK2.
  • ERKl and ERK2 When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation.
  • the ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK MAPK pathway is frequently activated in many tumors.
  • Ras genes which are upstream of one or both of ERKl and ERK2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors.
  • BRAF a serine-threonine kinase of the Raf family
  • kinase activity a serine-threonine kinase of the Raf family
  • such compounds have general Formula I:
  • such compounds have general Formula II:
  • Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by certain protein kinase-mediated events. Such diseases, disorders, or conditions include those described herein.
  • Compounds provided by this invention are also useful for the study of certain kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. Additional compounds and methods can be found in PCT patent application serial number PCT/US14/15256, filed February 7, 2014 and published as WO 2014/124230 on August 14, 2014 ("the '230 publication,” the entirety of which is hereby incorporated herein by reference). The '230 publication describes certain ER inhibitor compounds which covalently and irreversibly inhibit activity of one or both of ERKl and ERK2 kinases.
  • the present invention provides inhibitors of one or both of ERKl and ERK2 and conjugates thereof.
  • such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0013] In some embodiments such compounds have the structure of Formula I:
  • X, X', and X" are each independently O;
  • p, q, and r are each independently 0 or 1;
  • R 1 is -OR'
  • R' is -H, -CH 3 , -S0 3 H or -Glu
  • each Glu is a glucuronyl moiety
  • R 2 and R 3 are each independently -H, -OH, -OS0 3 H, -OGlu, -SR 5 , or:
  • R 2 and R 3 are taken together to form a double bond
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety;
  • R 2' is -H, or:
  • R 3 and R 3 are each -H, or:
  • R is -H, -OH, -OS0 3 H or -OGlu
  • each R 5 is independently selected from:
  • R x and R y are each independently -OH, -OSO 3 H, or -OGlu;
  • R z , R z' and R z" are each independently -H, -CH 3 , -OH, -OSO3H, or -OGlu; or
  • R z" and R 3 are taken together to form -0-;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • R 1 , R 4 , R x , R y , R z , R z' and R z" is -OH, -OS0 3 H or -OGlu; or (b) one of p, q, or r is 1.
  • X, X', and X" are each independently O;
  • p, q, and r are each independently 0 or 1;
  • R 1 is -OR'
  • R' is -H, -CH 3 , -S0 3 H or -Glu
  • each Glu is a glucuronyl moiety
  • R 2 and R 3 are each independently -H, -OH, -OS0 3 H, -OGlu, -SR 5 , or:
  • R 2 and R 3 are taken together to form a double bond
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety;
  • R 2 ' is -H, or:
  • R 3 and R 3 are each -H, or:
  • R 4 is -H, -OH, -OS0 3 H or -OGlu
  • each R 5 is independently selected from:
  • R 6 is -CH 3 , -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu;
  • R 7 is -CH 3 , -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu;
  • R x and R y are each independently -OH, -OS0 3 H, or -OGlu;
  • R z , R z' and R z" are each independently -H, -CH 3 , -OH, -OS0 3 H, or -OGlu; or
  • R z" and R 3 are taken together to form -0-;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • R 1 , R 4 , R x , R y , R z , R z' and R z" is -OH, -OSO3H or -OGlu;
  • R 6 and R 7 are -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu; or
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “carbocyclic” refers to a monocyclic C3-C8 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • aralkyl refers to a straight or branched aliphatic group in which one of the hydrogen atoms of the aliphatic is replaced by an aryl group, wherein the aliphatic group has from 1 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the aliphatic, the aryl, or both the aliphatic and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • amino acid fragment refers to a portion of an amino acid, such as by way of example only, the 20 common, genetically-encoded amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine), or a dipeptide, tripeptide or other polypeptide comprising a combination of the 20 common amino acids or a non-natural amino acid.
  • amino acids i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
  • the amino acid fragment is attached to a compound of Formula I or II via the side chain of the amino acid.
  • the amino acid fragment is a cysteine fragment wherein the remaining portion of a compound of Formula I or II is bound via a sulfur bond.
  • the amino acid fragment is a glutathione fragment wherein the remaining portion of a compound of Formula I or II is bound via a sulfur bond of the glutathione fragment.
  • the amino acid fragments are derived from beta-amino acids.
  • the amino acid fragments are derived from portions of polypeptides or proteins.
  • the amino acid fragment is attached to a compound of Formula I or II via the N-terminal or the acyl -terminal of the amino acid.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a "bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
  • lower alkyl refers to a Ci_ 4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a Ci_ 4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci_g (or Ci_ 6 ) saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • cycloalkylalkyl refers to a bivalent straight or branched aliphatic group that is substituted with a cycloalkyl group, wherein the aliphatic group has from 1 to 10 carbon atoms.
  • a cycloalkylalkyl group include -(CH 2 ) x -cyclopentyl, -(CH 2 ) x -cyclohexyl, - (CH 2 ) x -cycloheptyl, etc., wherein x is 1-10.
  • the aliphatic chain of a cycloalkylalkyl group may be straight or branched, for example, -(CH 2 ) y CH(CH 3 )(CH 2 ) y - cyclopentyl, -(CH 2 ) y CH(CH 3 )(CH 2 ) y -cyclohexyl, -(CH 2 ) y CH(CH 3 )(CH 2 ) y -cycloheptyl, etc., wherein y is 0-10.
  • the cycloalkyl ring of a cycloalkylalkyl group is saturated or partially unsaturated. Substituted cycloalkylalkyl groups may be substituted at the aliphatic, the cycloalkyl, or both the aliphatic and the cycloalkyl portions of the group.
  • halogen means F, CI, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, 1,3- dihydro-2H-benzo[d]imidazole-2-one, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroaryl refers to an straight or branched aliphatic group substituted by a heteroaryl, wherein the aliphatic group has from 1 to 10 carbon atoms and wherein the aliphatic and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • heterocyclylalkyl refers to a bivalent straight or branched aliphatic group that is substituted with a heterocyclyl moiety, wherein the aliphatic group has from 1 to 10 carbon atoms.
  • heterocyclylalkyl group examples include, without limitation, - (CH 2 ) x -piperidinyl, -(CH 2 ) x -piperazinyl, -(CH 2 ) x -pyrrolidinyl, -(CH 2 ) x -morpholinyl, -(CH 2 ) X - pyrrolidinyl, -(CH 2 ) x -tetrahydrofuranyl, -(CH 2 ) x -tetrahydropyranyl, etc., wherein x is 1-10.
  • the aliphatic chain of a heterocyclylalkyl group may be straight or branched, for example, -(CH 2 ) y CH(CH 3 )(CH 2 ) y -piperidinyl, -(CH 2 ) y CH(CH 3 )(CH 2 ) y -tetrahydrofuranyl, - (CH 2 ) y CH(CH 3 )(CH 2 ) y -tetrahydropyranyl, -(CH 2 ) y CH(CH 3 )(CH 2 ) y -morpholinyl, etc., wherein y is 0-10.
  • the heterocyclyl ring of a heterocyclylalkyl group is saturated or partially unsaturated.
  • Substituted heterocyclylalkyl groups may be substituted at the aliphatic, the heterocyclyl, or both the aliphatic and the heterocyclyl portions of the group.
  • alkoxy is -O-(aliphatic), wherein aliphatic is defined above.
  • alkoxyalkyl is -(aliphatic)-O-(aliphatic), wherein aliphatic is defined above.
  • An “amino” group is a radical of the formula -NH 2 .
  • An “alkylamino” group is a radical of the formula: -NH-aliphatic or -N(aliphatic) 2 , wherein each aliphatic is independently as defined above.
  • a "carboxy” group is a radical of the formula -C(0)OH.
  • aminocarbonyl is a radical of the formula -C(0)N(R ) 2 , -C(0)NH(R ) or -C(0)NH 2 , wherein each R is independently a substituted or unsubstituted aliphatic, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl group as defined herein.
  • acylamino is a radical of the formula: -NHC(0)(R ) or -N(alkyl)C(0)( R ), wherein each alkyl and R are independently as defined above.
  • alkylsulfonylamino is a radical of the formula: -NHS0 2 (R ) or
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR*, -(CH 2 ) 0 2 CH(OR*) 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0 2 C(0)R*, -(CH 2 ) 0 2 C(0)OH, -(CH 2 ) 0 2 C(0)OR*, -(CH 2 ) 0 2 SR*, -(CH 2 )o 2 SH, -(CH 2 )o 2 NH 2 , -(CH 2 ) 0 2 NHR*, -(CH 2 ) 0 2 NR* 2 , -N0 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 _ 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 -iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_ 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • isomeric e.g., enantiomeric, diastereomeric, and geometric (or conformational)
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety, R 1 of a provided compound comprises one or more deuterium atoms.
  • the term "irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protein kinase in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond) the target protein kinase, and therefore can become dissociated from the target protein kinase, an irreversible inhibitor will remain substantially bound to the target protein kinase once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme.
  • Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with the protein kinase target, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as "washout," experiments, and the use of labeling, such as radiolabeled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.
  • the present invention provides a compound of Formula I
  • X, X', and X" are each independently O;
  • p, q, and r are each independently 0 or 1;
  • R 1 is -OR'
  • R' is -H, -CH 3 , -S0 3 H or -Glu
  • each Glu is a glucuronyl moiety
  • R 2 and R 3 are each independently -H, -OH, -OS0 3 H, -OGlu, -SR 5 , or:
  • R 2 and R 3 are taken together to form a double bond
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety;
  • R 2' is -H, or:
  • R 4 is -H, -OH, -OSO 3 H or -OGlu
  • eac 5 is independently selected from:
  • R x and R y are each independently -OH, -OSO 3 H, or -OGlu;
  • R z , R z' and R z" are each independently -H, -CH 3 , -OH, -OSO3H, or -OGlu; or
  • R z" and R 3 are taken together to form -0-;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • R 1 , R 4 , R x , R y , R z , R z' and R z" is -OH, -OSO3H or -OGlu;
  • the present invention provides a compound of Formula II:
  • X, X', and X" are each independently O;
  • p, q, and r are each independently 0 or 1;
  • R 1 is -OR'
  • R' is -H, -CH 3 , -S0 3 H or -Glu
  • each Glu is a glucuronyl moiety
  • R 2 and R 3 are each independently -H, -OH, -OS0 3 H, -OGlu, -SR 5 , or:
  • R 2 and R 3 are taken together to form a double bond
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety;
  • R 2' is -H, or:
  • R 3 and R 3 are each -H, or:
  • R 4 is -H, -OH, -OSO 3 H or -OGlu;
  • eac 5 is independently selected from:
  • R 6 is -CH 3 , -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu;
  • R 7 is -CH 3 , -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu;
  • R x and R y are each independently -OH, -OS0 3 H, or -OGlu;
  • R z , R z' and R z" are each independently -H, -CH 3 , -OH, -OS0 3 H, or -OGlu; or
  • R z" and R 3 are taken together to form -0-;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • R 1 , R 4 , R x , R y , R z , R z' and R z" is -OH, -OSO3H or -OGlu;
  • R 6 and R 7 are -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu; or
  • glucuronyl moiety refers to a group having the structure:
  • an -OH group on a compound of Formula I or II is glucuronidated to a -OGlu group. In some embodiments, an -OH group of Formula I or II is sulfated to a -OSO 3 H group.
  • R w is H or . In some embodiments, R w is
  • R w is , wherein each of R 2 , R 2 , R 3 , R 3 , and R 3 are as defined above and herein.
  • R 1 is -OR'.
  • R' is -H, -CH 3 , - S0 3 H or -Glu.
  • R' is -H.
  • R' is selected from - CH 3 , -S0 3 H and -Glu.
  • R' is -CH 3 .
  • R' is -S0 3 H.
  • R' is -Glu. Accordingly, in some embodiments, R 1 is selected from -OH, -OCH 3 , -OS0 3 H, -OGlu.
  • R 1 is -OH. In some embodiments, R 1 is -OCH 3 . In some embodiments, R 1 is -OS0 3 H. In some embodiments, R 1 is -OGlu.
  • R 2 is selected from -H, -OH, -OS0 3 H -OGlu, and -SR 5 .
  • R 2 is -H.
  • R 2 is selected from -OH, -OS0 3 H and - OGlu.
  • R 2 is -OH.
  • R 2 is -OSO3H.
  • R 2 is -OGlu.
  • R 2 is -SR 5 .
  • R 3 is selected from -H, -OH, -OSO3H, -OGlu and -SR 5 .
  • R 3 is -H.
  • R 3 is selected from -OH, -OSO3H and - OGlu.
  • R 3 is -OH.
  • R 3 is -OSO3H.
  • R 3 is -OGlu.
  • R 2 is -SR 5 .
  • R 3 is -SR 5 . In some such
  • Such moiety is generally referred to glutathione fragment.
  • R 3 is -SR 5 , wherein R 5 is In
  • Such moiety is generally referred to as a cysteine-glycine fragment.
  • R 3 is -SR 5 , wherein R 5 is Such moiety is generally referred to as a cysteine fragment.
  • R 3 is -SR 5 , wherein R 5 is .
  • Such moiety is generally referred to as an N-acetyl cysteine fragment.
  • R 2 is H and R 3 is -SR 5 . In some such embodiments, R 5 is
  • R 3 is -SR 5 , wherein R 5 is
  • R is H and R is -SR , wherein R is
  • R 2 and R 3 are the same. In some embodiments, R 2 and R 3 are each -OH. In some embodiments, R 2 and R 3 are each -SO3H. In some embodiments, R 2 and R 3 are each -OGlu.
  • R 2 and R 3 are different. In some embodiments, one of R 2 and R 3 are different.
  • R 3 is -H and the other is -OH. In some embodiments, one of R 2 and R 3 is -H and the other is
  • one of R 2 and R 3 is -H and the other is -OGlu. In some embodiments, one of R 2 and R 3 is -OH and the other is -OGlu. In some embodiments, one of R 2 and R 3 is -OH and the other is -OSO3H.
  • R 2 is -OH and R 3 is -OGlu. In some embodiments, R 2 is - OGlu and R 3 is -OH. In some embodiments, R 2 is -OH and R 3 is -OSO3H. In some embodiments, R 2 is -OSO 3 H and R 3 is -OH. In some embodiments, each of R 2 and R 3 is - OSO3H. In some embodiments, each of R 2 and R 3 is -OGlu.
  • R 2 and R 3 are taken together to form a double bond.
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety.
  • R 2 is -H. In some embodiments, R 2 and R 2 are each -H. In some embodiments, R 2 is -OH and R 2 is -H. In some embodiments, R 2 is -OSO3H and R 2 is - H. In some embodiments, R 2 is -OGlu and R 2 is -H.
  • R 3 and R 3 are each -H. In some embodiments, R 3 is -OH
  • R and R are each -H.
  • R is -OSO3H and R and R are each -H.
  • R 4 is selected from -H, -OH, -OSO3H and -OGlu. In some embodiments, R 4 is -H. In some embodiments, R 4 is selected from -OH, -OSO3H and - OGlu. In some embodiments, R 4 is selected from -OH, -OSO3H and OGlu. In some embodiments, R 4 is -OH. In some embodiments, R 4 is -OSO 3 H. In some embodiments, R 4 is - OGlu.
  • R 6 is selected from -CH 3 , -CH 2 OH, -CH 2 OS0 3 H and - CH 2 OGlu. In some embodiments, R 6 is -CH 3 . In some embodiments, R 6 is selected from - CH 2 OH, -CH 2 OS0 3 H and -CH 2 OGlu. In some embodiments, R 6 is -CH 2 OH. In some embodiments, R 6 is -CH 2 OS0 3 H. In some embodiments, R 6 is -CH 2 OGlu.
  • R 7 is selected from -CH 3 , -CH 2 OH, -CH 2 OS0 3 H and - CH 2 OGlu. In some embodiments, R 7 is -CH 3 . In some embodiments, R 7 is selected from - CH 2 OH, -CH 2 OS0 3 H and -CH 2 OGlu. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is -CH 2 OS0 3 H. In some embodiments, R 7 is -CH 2 OGlu.
  • p, q, and r are each independently selected from 0 and 1. In some embodiments, one of p, q, and r is 1. In some embodiments, p is 1. In some embodiments, p is 0. In some embodiments, q is 1. In some embodiments, q is 0. In some embodiments, r is 1. In some embodiments, r is 0. In some embodiments, both p and q are 0. In some embodiments, both q and r are 0. In some embodiments, both p and r are 0. In some embodiments, each of p, q, and r are 0.
  • m is selected from 0, 1, 2, and 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • n is selected from 0, 1, and 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [0091] As defined generally above, R x is selected from -H, -OH, -OSO 3 H and -OGlu. In some embodiments, R x is -H. In some embodiments, R x is selected from -OH, -OSO 3 H and - OGlu. In some embodiments, R x is selected from -OH, -OSO 3 H and -OGlu. In some embodiments, R x is -OH. In some embodiments, R x is -OSO 3 H. In some embodiments, R x is - OGlu.
  • R y is selected from -H, -OH, -OSO 3 H and -OGlu. In some embodiments, R y is -H. In some embodiments, R y is selected from -OH, -OSO 3 sHi and - OGlu. In some embodiments, R y is selected from -OH, J
  • R y is -OH. In some embodiments, R y is -OSO 3 H. In some embodiments, R y is -
  • R z , R z and R z are each independently selected from -H, -CH 3 , -OH, -OSO 3 H and -OGlu. In some embodiments, R z , R z and R z are each independently selected from -CH 3 , -OH, -OSO 3 H and -OGlu. In some embodiments, at least one of R z , R z and R z is -OH. In some embodiments, one of R z , R z and R z is -CH 3 . In some embodiments, R z is -H.
  • R z is selected from -CH 3 , -OH, -OSO 3 H and -OGlu. In some embodiments, R z is -OH. In some embodiments, R z is -CH 3 . In some embodiments, R z is - OSO 3 H. In some embodiments, R z is -OGlu. In some embodiments, R z is -H. In some embodiments, R z is selected from -CH 3 , -OH, -OSO 3 H and -OGlu. In some embodiments, R z is -OH. In some embodiments, R z is -CH 3 . In some embodiments, R z is -OSO 3 H.
  • R z is -OGlu. In some embodiments, R z is -H. In some embodiments, R z is selected from -CH 3 , -OH, -OSO 3 H and -OGlu. In some embodiments, R z is -OH. In some embodiments, R z is -CH 3 . In some embodiments, R z is -OSO 3 H. In some embodiments, R z is -OGlu.
  • R z and R 3 are taken together to form -0-.
  • R w is R 3 0 , wherein each of R 1 , R 2 , R 2 , R 3 , R 3' , R 3" , R 4 , R z , R z' . R z" , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • at least one of R 2 and R 3 is -SR 5 and at least one of the following is true:
  • R 1 , R 4 , R x , R y , R z , R z' and R z" is -OH, -OSO 3 H or -OGlu; or
  • at least one of R 6 and R 7 , when present, is -CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu; or
  • R 3 is -SR 5 .
  • R 5 is
  • a compound of formula I or II is of any of the structures described above and herein, wherein the structure is prone to further oxidation.
  • a compound is of formula I or II, wherein m is 1 or 2 and each R x is -OH, such that the compound comprises a phenol or hydroquinone moiety.
  • m is 1 or 2 and each R x is -OH, such that the compound comprises a phenol or hydroquinone moiety.
  • m is 1 or 2 and each R x is -OH
  • the compound comprises a phenol or hydroquinone moiety.
  • a phenol or hydroquinone moiety may undergo further oxidation to afford the corresponding quinone configuration.
  • heteroaryl rings such as those of compounds of formula I or II may undergo similar such reactions, and that such further oxidized compounds are accordingly contemplated herein.
  • a compound is of formula I or II wherein R w is H.
  • a compound is of formula I or
  • a compound is of formula I or II wherein R 1 is - -OH.
  • a compound is of formula I or II wherein R 1 is - -OCH 3 .
  • a compound is of formula I or II wherein R 1 is - -OS0 3 H.
  • a compound is of formula I or II wherein R 1 is - -OGlu.
  • a compound is of formula I or II wherein R 4 is - -H.
  • a compound is of formula I or II wherein R 4 is - -OH.
  • a compound is of formula I or II wherein R 4 is - -OS0 3 H.
  • a compound is of formula I or II wherein R 4 is - -OGlu.
  • a compound is of formula I or II wherein R x is - -OH.
  • a compound is of formula I or II wherein R x is - -OS0 3 H.
  • a compound is of formula I or II wherein R x is - -OGlu.
  • a compound is of formula I or II wherein m is 0
  • a compound is of formula I or II wherein m is 1
  • a compound is of formula I or II wherein m is 2
  • a compound is of formula I or II wherein m is 3
  • a compound is of formula I or II wherein R y is - OH.
  • a compound is of formula I or II wherein R y is - OSO 3 H.
  • a compound is of formula I or II wherein R y is - OGlu.
  • a compound is of formula I or II wherein n is 0.
  • a compound is of formula I or II wherein n is 1.
  • a compound is of formula I or II wherein n is 2.
  • a compound is of formula I or II wherein p is 1.
  • a compound is of formula I or II wherein q is 1.
  • a compound is of formula I or II wherein r is 1.
  • a compound is of formula I or II wherein R z , R z and R z are each -H.
  • a compound is of formula I or II wherein one of R z , R z or R z is -CH 3 , -OH, -OS0 3 H, or -OGlu.
  • R 2 and R 3 are taken together to form a double bond. Accordingly, in some embodiments, the present invention provides a compound of Formula I-a:
  • a compound is of formula I-a, wherein at least one of R 1 , R 4 , R x , and R y is independently selected from -OH, -OSO3H and -OGlu.
  • a compound is of formula I-a, wherein at least one of R 1 , R 4 , R x , and R y is -OH.
  • a compound is of formula I-a, wherein at least one of R 1 , R 4 , R x , and R y is - OSO3H.
  • a compound is of formula I-a, wherein at least one of R 1 , R 4 , R x , and R y is -OGlu.
  • a compound is of formula I-a and R 1 is -OH, -OSO3H or - OGlu. In some embodiments, a compound is of formula I-a and R 1 is -OH. In some embodiments, a compound is of formula I-a and R 1 is -OSO3H. In some embodiments, a compound is of formula I-a and R 1 is -OGlu.
  • a compound is of formula I-a and n is 0. In some embodiments, a compound is of formula I-a and n is 1. In some embodiments, a compound is of formula I-a and n is 2. In some embodiments, a compound is of formula I-a and m is 0. In some embodiments, a compound is of formula I-a and m is 1. In some embodiments, a compound is of formula I-a and m is 2. In some embodiments, a compound is of formula I-a and m is 3.
  • At least one of m or n is 0 and R 1 is OH. In certain embodiments, both m and n are 0 and R 1 is OH.
  • a compound is of formula I-a and at least one of p, q, and r is
  • a compound is of formula I-a and p is 1. In some embodiments, a compound is of formula I-a and q is 1. In some embodiments, a compound is of formula I-a and r is 1.
  • a compound is of formula I-a and R 1 is -OMe.
  • a compound is of formula I-a, wherein R 1 is -OMe and at least one of p, q, and r is 1. In some embodiments, a compound is of formula I-a, wherein R 1 is - OMe and p is 1. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe and and q is 1. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe and r is 1.
  • a compound is of formula I-a, wherein R 1 is -OMe and m is 1,
  • a compound is of formula I-a, wherein R 1 is -OMe and m is 1. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe and m is 2. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe and m is 3. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe, m is 1, 2, or 3, and each R x is -OH. In some embodiments, a compound is of formula I-a, wherein R 1 is -OMe, m is 1, 2, or 3, and each R x is -OSO3H. In some embodiments, a compound is of formula I-a, wherein R 1 is - OMe, m is 1, 2, or 3, and each R x is -OGlu.
  • a compound is of formula I-a, wherein R 1 is -OMe, m is 1, and R x is -OH.
  • a compound is of formula I-a, wherein R 1 is -OMe, m is 1, and R x is -OSO3H.
  • a compound is of formula I-a, wherein R 1 is - OMe, m is 1, and R x is -OGlu.
  • a compound is of formula I-a, wherein R z , R z and R z are each -H.
  • a compound is of formula I-a, wherein one of R z , R z or R z is -
  • the compound is of formula I-a, wherein R 4 is hydrogen.
  • the present invention provides a compound of formula I-a of any one of the followin formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a having any one of the structures depicted below in Table 1 :
  • the present invention provides a compound of formula I-a an one of the following formulae:
  • each of R 1 , R 4 , R z , R z , R z , R x , R y , X, X', X", m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a having any one of the structures depicted below in Table 2:
  • the present invention provides a compound of formula I-a of the following formula:
  • the present invention provides a compound of formula I-a of the following formula:
  • R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R 1 is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • each of R 4 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • each of R 4 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • each of R 4 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula I-a of the following formula:
  • R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula I-a having any one of the structures depicted below in Table 3 :
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a of any one of the following formulae:
  • the present invention provides a compound of formula I-a having any one of the structures depicted below in Table 4:
  • R 2 and R 3 do not form a double bond. Accordingly, in some embodiments, the present invention provides a compound of Formula I-b:
  • R x , R y , X, X', X", m, n, p, q, and r are as defined herein, and wherein:
  • R 2 and R 3 are each independently -H, -OH, -OSO 3 H, -OGlu, or -SR 5 , or:
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety.
  • the present invention provides a compound of Formula I-b wherein R 1 is -OMe.
  • the present invention provides a compound of Formula I-b wherein R 1 is selected from -OH, -OSO 3 H and -OGlu.
  • the present invention provides a compound of Formula I-b wherein m is 1.
  • the present invention provides a compound of Formula I-b wherein n is 1.
  • the present invention provides a compound of Formula I-b wherein p is 1.
  • the present invention provides a compound of Formula I-b wherein q is 1.
  • the present invention provides a compound of Formula I-b wherein r is 1.
  • the present invention provides a compound of Formula I-b wherein R z , R z and R z are each -H. [00177] In some embodiments, the present invention provides a compound of Formula I-b wherein one of R z , R z' or R z " is -CH 3 , -OH, -OS0 3 H, or -OGlu.
  • the present invention provides a compound of Formula I-b wherein R 2 is -H.
  • the present invention provides a compound of Formula I-b wherein R 2 is -OH.
  • the present invention provides a compound of Formula I-b wherein R 2 is -OS0 3 H.
  • the present invention provides a compound of Formula I-b wherein R 2 is -OGlu.
  • the present invention provides a compound of Formula I-b wherein R 3 is -H.
  • the present invention provides a compound of Formula I-b wherein R 3 is -OH.
  • the present invention provides a compound of Formula I-b wherein R 3 is -OS0 3 H.
  • the present invention provides a compound of Formula I-b wherein R 3 is -OGlu.
  • the present invention provides a compound of Formula I-b wherein R 2 and R 3 are the same.
  • the present invention provides a compound of Formula I-b wherein R 2 and R 3 are -OH.
  • the present invention provides a compound of Formula I-b wherein R 2 and R 3 are different. In some such embodiments, the present invention provides a compound of Formula I-b wherein R 2 is H. In some such embodiments, the present invention provides a compound of Formula I-b wherein R 2 is H and R 3 is -SR 5 . In some such
  • R 5 such embodiments, R 5 is . In some such embodiments, R 5 is [00189]
  • the present invention provides a compound of Formula I-b wherein R 4 is H. In some embodiments, the present invention provides a compound of Formula
  • R 2 , R 2' , R 3 , R 3' , and R 3" is not hydrogen.
  • a compound is of formula I-b and R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety.
  • R 2 and R 3 are each independently -H, -OH, -OSO 3 H, -OGlu, or -SR 5 .
  • a compound is of formula I-b and at least one of R 2 and R 3 is - OH. In some embodiments, a compound is of formula I-b and both of R 2 and R 3 are -OH. In some embodiments, a compound is of formula I-b and at least one of R 2 and R 3 is -OS0 3 H. In some embodiments, a compound is of formula I-b and both of R 2 and R 3 are -OSO3H. In some embodiments, a compound is of formula I-b and at least one of R 2 and R 3 is -OGlu. In some embodiments, a compound is of formula I-b and both of R 2 and R 3 are -OGlu.
  • one of R 2 or R 3 is -OH and the other of R 2 or R 3 is -OS0 3 H. In some embodiments, one of R 2 or R 3 is -OH and the other of R 2 or R 3 is -OGlu. In some embodiments, one of R 2 or R 3 is -OGlu and the other of R 2 or R 3 is -OS0 3 H.
  • a compound is of formula I-b, wherein R 2 is -OH, -OS0 3 H, or -OGlu, and the resulting chiral center of the adjacent carbon atom is in the (S) configuration.
  • a compound is of formula I-b, wherein R 2 is -OH, -OS0 3 H, or -OGlu, and the resulting chiral center of the adjacent carbon atom is in the (R) configuration.
  • a compound is of formula I-b, wherein R 2 is -OH and the resulting chiral center of the adjacent carbon atom is in the (S) configuration.
  • a compound is of formula I-b, wherein R 2 is -OH and the resulting chiral center of the adjacent carbon atom is in the (R) configuration.
  • a compound is of formula I-b wherein at least one of R 2 and R 3 is -OH and R 1 is -OMe. In some embodiments, a compound is of formula I-b wherein both of R 2 and R 3 are -OH and R 1 is -OMe.
  • a compound is of formula I-b wherein at least one of R 2 and R 3 is -OH and R 4 is -H. In some embodiments, a compound is of formula I-b wherein both of R 2 and R 3 are -OH and R 4 is -H. [00196] In some embodiments, a compound is of formula I-b, wherein R 3 is -SR 5 . In some embodiments, a compound is of formula I-b, wherein R 3 is -SR 5 , and each of R 2 and R 2 are H.
  • a compound is of formula I-b, wherein R 3 is -SR 5 and R 5 is
  • a compound is of formula I-b, wherein R 3
  • a compound is of formula I-b,
  • R 3 is -SR 5 and R 5 is In some embodiments, a compound is of formula I-b,
  • R 3 is -SR 5 and R 5 is
  • a compound is of formula I-b, wherein R 3 is -SR 5 and R 1 is - OMe. In some embodiments, a compound is of formula I-b, wherein R 3 is -SR 5 and R 4 is -H.
  • the present invention provides a compound of formula I-b of the following formula:
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 1 , R 2 , R 3 , R x , R y , m and n is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 2 , R 3 , R x , and m is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • R 2 , R 3 , R y , and n is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 2 and R 3 is as defined above and described herein.
  • the present invention provides a compound of formula I-b of either of the following formulae:
  • the present invention provides a compound of formula I-b of either of th following formulae:
  • R 3 is as defined above and described herein.
  • the present invention provides a compound of formula I-b having any one of the structures depicted below in Table 5 :
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 1 , R 2 , R 4 , R 5 , R z , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • R 1 , R 2 , R 4 , R 5 , R x , R y , m, and n is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • R 2 , R 5 , R y , and n is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 2 , R 5 , R x , and m is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • each of R 2 and R 5 is as defined above and described herein.
  • the present invention provides a compound of formula I-b of the following formula:
  • R 5 is as defined above and described herein.
  • the present invention provides a compound of formula I-b having any one of the structures depicted below in Table 6:
  • the present invention provides a compound of Formula I-c:
  • R 1 , R 4 , R z , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • a compound is of formula I-c, wherein R z is -H.
  • a compound is of formula I-c, wherein R 1 is -OMe.
  • a compound is of formula I-c, wherein R 1 is selected from -
  • a compound is of formula I-c, wherein R 4 is -H.
  • a compound is of formula I-c, wherein m is 1.
  • a compound is of formula I-c, wherein n is 1.
  • a compound is of formula I-c, wherein p is 1.
  • a compound is of formula I-c, wherein q is 1.
  • a compound is of formula I-c, wherein r is 1.
  • a compound is of formula I-c, wherein R z , R z and R z are each
  • a compound is of formula I-c, wherein one of R z , R z or R z is - CH 3 , -OH, -OS0 3 H, or -OGlu.
  • a compound is of formula I-c, wherein R z is -H and wherein R 1 is -OMe. In some embodiments, a compound is of formula I-c, wherein R z is -H and wherein R 4 is -H.
  • the present invention provides a compound of Formula I-c of the following formula:
  • R 1 , R 4 , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of Formula I-c of the following formula:
  • R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of Formula I-c of the following formula:
  • R x , R y , m, and n is as defined above and described herein.
  • the present invention provides a compound of Formula I-c of the following formula:
  • R y and n is as defined above and described herein.
  • the present invention provides a compound of Formula I-c of the following formula:
  • R x and m is as defined above and described herein.
  • the present invention provides a compound of formula I-c having the structure depicted below in Table 7:
  • R 2 and R 3 are taken together to form a double bond. Accordingly, in some embodiments, the present invention provides a compound of Formula Il-a:
  • each of R 1 , R 4 , R 6 , R 7 , R z , R z' , R z" , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • a compound is of formula Il-a, wherein at least one of R 1 , R 4 , R x , and R y is independently selected from -OH, -OSO 3 H and -OGlu.
  • a compound is of formula Il-a, wherein at least one of R 1 , R 4 , R x , and R y is -OH.
  • a compound is of formula Il-a, wherein at least one of R 1 , R 4 , R x , and R y is - OSO3H.
  • a compound is of formula Il-a, wherein at least one of R 1 , R 4 , R x , and R y is -OGlu.
  • a compound is of formula Il-a and R 1 is -OH, -OSO3H or - OGlu. In some embodiments, a compound is of formula Il-a and R 1 is -OH. In some embodiments, a compound is of formula Il-a and R 1 is -OSO3H. In some embodiments, a compound is of formula Il-a and R 1 is -OGlu.
  • a compound is of formula Il-a and n is 0. In some embodiments, a compound is of formula Il-a and n is 1. In some embodiments, a compound is of formula Il-a and n is 2. In some embodiments, a compound is of formula Il-a and m is 0. In some embodiments, a compound is of formula Il-a and m is 1. In some embodiments, a compound is of formula Il-a and m is 2. In some embodiments, a compound is of formula Il-a and m is 3.
  • At least one of m or n is 0 and R 1 is OH. In certain embodiments, both m and n are 0 and R 1 is OH.
  • a compound is of formula Il-a and at least one of p, q, and r is 1. In some embodiments, a compound is of formula Il-a and p is 1. In some embodiments, a compound is of formula Il-a and q is 1. In some embodiments, a compound is of formula Il-a and r is 1.
  • a compound is of formula Il-a and R 1 is -OMe.
  • a compound is of formula Il-a, wherein R 1 is -OMe and at least one of p, q, and r is 1. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and p is 1. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and and q is 1. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and r is 1.
  • a compound is of formula Il-a, wherein R 1 is -OMe and m is 1, 2, or 3. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and m is 1. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and m is 2. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe and m is 3. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe, m is 1, 2, or 3, and each R x is -OH.
  • a compound is of formula Il-a, wherein R 1 is -OMe, m is 1, 2, or 3, and each R x is -OSO 3 H. In some embodiments, a compound is of formula Il-a, wherein R 1 is -OMe, m is 1, 2, or 3, and each R x is -OGlu.
  • a compound is of formula Il-a, wherein R 1 is -OMe, m is 1, and R x is -OH. In certain embodiments, a compound is of formula Il-a, wherein R 1 is -OMe, m is 1, and R x is -OSO 3 H. In certain embodiments, a compound is of formula Il-a, wherein R 1 is - OMe, m is 1, and R x is -OGlu.
  • the compound is of formula Il-a, wherein R 4 is hydrogen.
  • the compound is of formula Il-a, wherein R 6 is selected from -CH 3 , -CH 2 OH, -CH 2 SO 3 H, and -CH 2 OGlu. In some embodiments, the compound is of formula Il-a, wherein R 6 is -CH 3 . In some embodiments, the compound is of formula Il-a, wherein R 6 is selected from -CH 2 OH, -CH 2 S0 3 H, and -CH 2 OGlu. In some embodiments, the compound is of formula Il-a, wherein R 6 is selected from -CH 2 OH, -CH 2 OSO 3 H, and -CH 2 OGlu.
  • the compound is of formula Il-a, wherein R 6 is -CH 2 OH. In some embodiments, the compound is of formula Il-a, wherein R 6 is -CH 2 OSO 3 H. In some embodiments, the compound is of formula Il-a, wherein R 6 is -CH 2 OGlu.
  • the compound is of formula Il-a, wherein R 7 is selected from -CH 3 , -CH 2 OH, -CH 2 SO 3 H, and -CH 2 OGlu. In some embodiments, the compound is of formula Il-a, wherein R 7 is -CH 3 . In some embodiments, the compound is of formula Il-a, wherein R 7 is selected from -CH 2 OH, -CH 2 S0 3 H, and -CH 2 OGlu.
  • the compound is of formula Il-a, wherein R 7 is selected from -CH 2 OH, -CH 2 OS0 3 H, and -CH 2 OGluIn some embodiments, the compound is of formula Il-a, wherein R 7 is -CH 2 OH. In some embodiments, the compound is of formula Il-a, wherein R 7 is -CH 2 OSO 3 H. In some embodiments, the compound is of formula Il-a, wherein R 7 is -CH 2 OGlu.
  • the compound is of formula Il-a, wherein R z , R z and R z are each -H.
  • the compound is of formula Il-a, wherein one of R z , R z or R z is -CH 3 , -OH, -OSO 3 H, or -OGlu.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • R 1 , R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • each of R 1 , R 4 , R 6 , R 7 , R z , R z , R z , R y , X, X', X", n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • each of R 6 , R 7 , R z , R z , R y , X, X', X", n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • the present invention provides a compound of formula Il-a having any one of the structures depicted below in Table 8:
  • the present invention provides a compound of formula II, wherein the compound is other than a compound depicted in Table 8.
  • the present invention provides a compound of formula Il-a of either of the following formulae:
  • each of R 1 , R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of either of the following formulae:
  • each of R 1 , R 4 , R 6 , R 7 , R z , R z , R z , R x , X, X', X", m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of either of the following formulae:
  • the present invention provides a compound of formula Il-a of either of the following formulae:
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 1 , R 6 , R 7 , R x , R y , X, X', X", n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a the following formula:
  • each of R 6 , R 7 , R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • R 1 , R 6 , and R 7 are as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R z , R z , R x , R y , X, X', X", n, m, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of the following formula:
  • each of R 6 , R 7 , R x , R y , n, and m is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • R 1 , R 6 , R 7 , R x , R y , m, and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • R 6 , R 7 , R x , R y , m, and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • the present invention provides a compound of formula Il-a of any one of the following formulae:
  • R 2 and R 3 do not form a double bond. Accordingly, in some embodiments, the present invention provides a compound of Formula Il-b:
  • R z , R x , R y , X, X', X", m, n, p, q, and r is as defined herein, and wherein:
  • R 2 and R 3 are each independently -H, -OH, -OSO 3 H, -OGlu, or -SR 5 , or:
  • R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety.
  • the present invention provides a compound of Formula Il-b wherein at least one of R 2 , R 2' , R 3 , R 3' , and R 3" is not hydrogen.
  • the present invention provides a compound of Formula Il-b wherein R 1 is -OMe.
  • the present invention provides a compound of Formula Il-b wherein R 1 is selected from -OH, -OSO 3 H and -OGlu.
  • the present invention provides a compound of Formula Il-b wherein m is 1.
  • the present invention provides a compound of Formula Il-b wherein n is 1.
  • the present invention provides a compound of Formula Il-b wherein p is 1.
  • the present invention provides a compound of Formula Il-b wherein q is 1.
  • the present invention provides a compound of Formula Il-b wherein r is 1.
  • the present invention provides a compound of Formula Il-b wherein R z , R z and R z are each -H.
  • the present invention provides a compound of Formula Il-b wherein one of R z , R z' or R z " is -CH 3 , -OH, -OS0 3 H, or -OGlu.
  • the present invention provides a compound of Formula Il-b wherein R 2 is -H.
  • the present invention provides a compound of Formula Il-b wherein R 2 is -OH.
  • the present invention provides a compound of Formula Il-b wherein R 2 is -OS0 3 H.
  • the present invention provides a compound of Formula Il-b wherein R 2 is -OGlu.
  • the present invention provides a compound of Formula Il-b wherein R 3 is -H.
  • the present invention provides a compound of Formula Il-b wherein R 3 is -OH.
  • the present invention provides a compound of Formula Il-b wherein R 3 is -OS0 3 H.
  • the present invention provides a compound of Formula Il-b wherein R 3 is -OGlu.
  • the present invention provides a compound of Formula Il-b wherein R 2 and R 3 are the same.
  • the present invention provides a compound of Formula Il-b wherein R 2 and R 3 are different. In some such embodiments, the present invention provides a compound of Formu -b wherein R 2 is H. In some such embodiments, R 3 is -SR 5 . In some
  • R 3 is - SR 5 wherein R 5 is In some such embodiments, R 3 is SR 5 wherein R 5 is
  • a compound is of formula Il-b and R 2 and R 3 are taken together with their intervening atoms to form an epoxide moiety.
  • R 2 and R 3 are each independently -H, -OH, -OSO3H, -OGlu, or -SR 5 .
  • a compound is of formula Il-b and at least one of R 2 and R 3 is -OH. In some embodiments, a compound is of formula Il-b and both of R 2 and R 3 are -OH. In some embodiments, a compound is of formula Il-b and at least one of R 2 and R 3 is -OSO3H. In some embodiments, a compound is of formula Il-b and both of R 2 and R 3 are -OSO3H. In some embodiments, a compound is of formula Il-b and at least one of R 2 and R 3 is -OGlu. In some embodiments, a compound is of formula Il-b and both of R 2 and R 3 are -OGlu.
  • one of R 2 or R 3 is -OH and the other of R 2 or R 3 is -OSO3H. In some embodiments, one of R 2 or R 3 is -OH and the other of R 2 or R 3 is -OGlu. In some embodiments, one of R 2 or R 3 is -OGlu and the other of R 2 or R 3 is -OSO 3 H.
  • a compound is of formula Il-b, wherein R 2 is -OH, -OSO3H, or -OGlu, and the resulting chiral center of the adjacent carbon atom is in the (S) configuration.
  • a compound is of formula Il-b, wherein R 2 is -OH, -OSO 3 H, or -OGlu, and the resulting chiral center of the adjacent carbon atom is in the (R) configuration.
  • a compound is of formula Il-b, wherein R 2 is -OH and the resulting chiral center of the adjacent carbon atom is in the (S) configuration.
  • a compound is of formula Il-b, wherein R 2 is -OH and the resulting chiral center of the adjacent carbon atom is in the (R) configuration.
  • a compound is of formula Il-b wherein at least one of R 2 and R 3 is -OH and R 1 is -OMe. In some embodiments, a compound is of formula Il-b wherein both of R 2 and R 3 are -OH and R 1 is -OMe.
  • a compound is of formula Il-b wherein R 4 is H.
  • a compound is of formula Il-b wherein at least one of R 2 and
  • R 3 is -OH and R 4 is -H.
  • a compound is of formula Il-b wherein both of R 2 and R 3 are -OH and R 4 is -H.
  • a compound is of formula Il-b, wherein R 3 is -SR 5 .
  • a compound is of formula Il-b, wherein R 3 is -SR 5 , and each of R 2 and R 2 are H.
  • a compound is of formula Il-b, wherein R 3 is -SR 5 and R 5 is
  • a compound is of formula Il-b, wherein R 3
  • a compound is of formula Il-b,
  • R 3 is -SR 5 and R 5 is some embodiments, a compound is of formula II-
  • a compound is of formula Il-b, wherein R 3 is -SR 5 and R 1 is - OMe. In some embodiments, a compound is of formula Il-b, wherein R 3 is -SR 5 and R 4 is -H.
  • a compound is of formula Il-b, wherein R 6 is selected from - CH 2 OH, -CH 2 OSO 3 H, or -CH 2 OGlu.
  • a compound is of formula Il-b, wherein R 7 is selected from - CH 2 OH, -CH 2 OS0 3 H, or -CH 2 OGlu.
  • the present invention provides a compound of formula Il-b of the following formula:
  • each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • each of R 1 , R 2 , R 3 , R 6 , R 7 , R x , R y , m and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 2 , R 3 , R 6 , R 7 , R y , and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 2 , R 3 , R 6 , and R 7 is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of either of the following formulae:
  • R 2 , R 3 , R 6 , and R 7 is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of either of th following formulae:
  • R 3 , R 6 , and R 7 is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • each of R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R z , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R x , R y , m, and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 2 , R 5 , R 6 , R 7 , R y , and n is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • each of R 2 , R 5 , R 6 , R 7 , R x , and m is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 2 , R 5 , R 6 , and R 7 is as defined above and described herein.
  • the present invention provides a compound of formula Il-b of the following formula:
  • R 5 , R 6 , and R 7 are as defined above and described herein.
  • the present invention provides a compound of Formula II-c:
  • X, X', X", m, n, p, q, and r is as defined above and described herein.
  • a compound is of formula II-c, wherein R z is -H.
  • a compound is of formula II-c, wherein R 1 is -OMe.
  • a compound is of formula II-c, wherein R 1 is selected from -
  • a compound is of formula II-c, wherein R 4 is -H.
  • a compound is of formula II-c, wherein R z is -H and wherein R 1 is -OMe. In some embodiments, a compound is of formula II-c, wherein R z is -H and wherein R 4 is -H.
  • a compound is of formula II-c, wherein R 6 is selected from - CH 2 OH, -CH 2 OSO 3 H, or -CH 2 OGlu.
  • a compound is of formula II-c, wherein R 7 is selected from - CH 2 OH, -CH 2 OSO 3 H, or -CH 2 OGlu.
  • a compound is of formula II-c, wherein m is 1.
  • a compound is of formula II-c, wherein n is 1.
  • a compound is of formula II-c, wherein p is 1.
  • a compound is of formula II-c, wherein q is 1.
  • a compound is of formula II-c, wherein r is 1.
  • a compound is of formula II-c, wherein R z , R z and R z are each -H. [00335] In some embodiments, a compound is of formula II-c, wherein one of R z , R z or R z is -CH 3 , -OH, -OS0 3 H, or -OGlu.
  • the present invention provides a compound of Formula II-c of the following formula:
  • each of R 1 , R 4 , R 6 , R 7 , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of Formula II-c of the following formula:
  • each of R 6 , R 7 , R z , R z , R x , R y , X, X', X", m, n, p, q, and r is as defined above and described herein.
  • the present invention provides a compound of Formula II-c of the following formula:
  • each of R 6 , R 7 , R x , R y , m, and n is defined above and described herein.
  • the present invention provides a compound of Formula II-c the following formula:
  • R 6 , R 7 , R y and n is as defined above and described herein.
  • the present invention provides a compound of Formula II-c of the following formula:
  • each of R 6 , R 7 , R x and m is as defined above and described herein.
  • the present invention provides any compound described above and herein, or a pharmaceutically acceptable salt thereof.
  • the present invention provides any compound described above and herein in isolated form.
  • the present invention provides a composition comprising a compound of Formula I or Formula II, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
  • compounds of Formula I or II, and pharmaceutically acceptable salts thereof described herein are inhibitors of one or both of ERKl and ERK2.
  • ERK is one of the key components in the RAS- RAF-MEK-ERK MAPK pathway and that ERKl and ERK2 are downstream nodes within the MAPK pathway.
  • an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • ERK is a downstream target
  • ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway.
  • RAF or MEK utilized in the treatment of K-RAS and B- RAF mutant tumors have resulted in such drug resistance.
  • drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors).
  • Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
  • the activity of a compound of Formula I or II, or a pharmaceutically acceptable salt thereof, as an inhibitor of one or both of an ERKl and ERK2 kinase, or a mutant thereof may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of downstream phosphorylation, changes in gene expression, subsequent functional markers and consequences, and/or kinase activity of one or both of activated ERKl and ERK2 kinase, or a mutant thereof. Alternate in vitro assays quantitate the ability of the test compound to bind to one or both of ERKl and ERK2.
  • Test compound binding may be measured by radiolabeling the test compound prior to binding, isolating one or both of the compound / ERKl complex and the compound / ERK2 complex, and determining the amount of radiolabel bound.
  • test compound binding may be determined by running a competition experiment where test compounds are incubated with one or both of ERKl and ERK2 kinase bound to known radioligands.
  • Test compound binding may be determined by competition with an ERK covalent probe that is amenable to further functionalization with a detection probe, such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification
  • the term "measurably inhibit”, as used herein means a measurable change in one or both of ERKl and ERK2 protein kinase activity between a sample comprising a provided composition, and one or both of an ERKl and ERK2 protein kinase and an equivalent sample comprising one or both of ERKl and ERK2 protein kinase in the absence of a provided composition.
  • Such measurements of protein kinase activity are known to one of ordinary skill in the art and include those methods set forth herein below and/or in the Examples of the '230 publication.
  • a compound of Formula I or II, or a pharmaceutically acceptable salt thereof is an inhibitor of one or both of ER 1 and ERK2 protein kinases, and ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role.
  • Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERK1 and ERK2.
  • Such diseases, conditions, or disorders may also be referred to herein as an "ERK1- or ERK2- mediated disease, condition, or disorder.”
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder, wherein said method comprises administering to a patient in need thereof a compound of the present invention.
  • the present invention relates to a method of inhibiting one or both of ERKl and ERK2 protein kinase activity in a patient comprising the step of administering to said patient a composition comprising a compound of the present invention.
  • the present invention provides a method for treating a disease, condition, or disorder mediated by one or both of ERKl and ERK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound of the present invention.
  • the present invention provides a method for overcoming drug resistance to Raf or MEK inhibitors, comprising the step of administering to a patient an inhibitor compound of one or both of ERKl and ERK2, such as a compound of the present invention.
  • the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
  • the term “resistance” may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein.
  • the term “resistance” may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a composition comprising a compound of the present invention.
  • General diseases, conditions, or disorders treated by a compound of the present invention include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
  • the present invention relates to a method of treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone -related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention.
  • the cancer is recurring.
  • the cancer is refractory.
  • the cancer is metastatic.
  • the cancer is locally advanced.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer.
  • the cancer is a MAPK pathway-mediated cancer.
  • the cancer is a BRAF-mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the RAS-mutated cancer is an NRAS-mutated cancer, including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS Q61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular carcinoma (HCC)) and biliary passage carcinoma), kidney carcinoma, liver carcinoma (e.g.,
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-Hodgkin's lymphoma.
  • a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; oesophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung,
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is BRAF v600 -mutated melanoma.
  • the melanoma is a RAS-mutated melanoma. In some embodiments, the melanoma is NRAS- mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib- resistant, dabrafenib-resistant, etc.) melanoma. In certain embodiments, the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF -mutated melanoma. In some embodiments, the melanoma is relapsed. In some embodiments, the melanoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is colorectal cancer.
  • the colorectal cancer is locally advanced.
  • the colorectal cancer is metastatic.
  • the colorectal cancer is a BRAF- mutated colorectal cancer.
  • the colorectal cancer is a BRAF v600 -mutated colorectal cancer.
  • the colorectal cancer is a RAS-mutated colorectal cancer.
  • the colorectal cancer is a KRAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a NRAS-mutated colorectal cancer. In some embodiments, the colorectal cancer is relapsed. In some embodiments, the colorectal cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS- mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS-mutated pancreatic cancer.
  • the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the pancreatic cancer is relapsed.
  • the pancreatic cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF- mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer is relapsed.
  • the papillary thyroid cancer is refractory.
  • the papillary thyroid cancer includes undifferentiated or dedifferentiated histology.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the lung cancer is a KRAS-mutated lung cancer, including, but not limited to, KRAS W , KRAS ,or KRAS Q61L/H/R
  • the lung cancer is relapsed.
  • the lung cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • AML acute monocytic leukemia
  • AML-M5 acute lymphoblastic leukemia
  • a leukemia is acute T cell leukemia. In certain embodiments, a leukemia is myelomonoblastic leukemia. In certain embodiments, a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is a RAS- mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • the multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the multiple myeloma is relapsed.
  • the multiple myeloma is refractory.
  • the present invention relates to a method of treating a cancer, wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is hepatocellular carcinoma (HCC). In certain embodiments, the HCC is locally advanced.
  • HCC hepatocellular carcinoma
  • the HCC is metastatic. In certain embodiments, the HCC is a RAS-mutated HCC. In certain embodiments, the HCC is KRAS-mutated HCC. In certain embodiments, the HCC is a KRAS- mutated HCC, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R . In some embodiments, the hepatocellular carcinoma is relapsed. In some embodiments, the hepatocellular carcinoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising a compound of the present invention, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • a composition comprising a compound of the present invention, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • the compounds and compositions, according to the method of the present invention are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting one or both of ER 1 and ERK2 kinase, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting one or both of ERK1 and ERK2 kinase, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of one or both of ER 1 and ERK2, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting one or both of ER 1 and ERK2 kinase, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting one or both of ERK1 and ERK2 kinase, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the activity is inhibited irreversibly by covalently modifying Cys 183 of ERKl .
  • the activity is inhibited irreversibly by covalently modifying Cys 166 of ERK2. In certain embodiments, the activity is inhibited irreversibly by covalently modifying Cys 183 of ERKl and Cys 166 of ERK2.
  • the present invention provides a method for treating a disease, disorder, or condition mediated by one or both of ERKl and ERK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
  • LC-MS was recorded on the Agilent Technology LC-1200 system, and quadrupole MS model-6120.
  • Intact protein Erkl from Millipore (Cat. No. 14-439) was incubated for 60 min. at room temperature with a 10-fold excess of test compound to protein. 4 ⁇ ⁇ aliquots of the resulting mixture were diluted with 15 ⁇ ⁇ of 0.2% TFA prior to micro C4 ZipTipping directly onto the MALDI target using sinapinic acid as the desorption matrix (10 mg/ml in 0.1% TFA:Acetonitrile 50:50, v/v). The centroid mass of the target protein in the control sample was compared with the centroid mass of the target protein incubated with compound.
  • ERK1 enzyme 14-439-K
  • 5X ATP AS001A
  • ST17-Sox conjugated peptide substrate KNZ1 171C
  • IX kinase reaction buffer consisting of 20 mM Tris, pH 7.5, 5 mM MgCl 2 , 1 mM EGTA, 5 mM ⁇ -glycerophosphate, 5% glycerol (10X stock, KB001A) and 0.2 mM DTT.
  • the protocol below describes an assay to measure the kinase activity of ERKl/2 to phosphorylate a substrate, p90RSK, in the presence or absence of a test compound.
  • This experiment was conducted using a Mesoscale Discovery plate. The day before the assay, HT29 cells were split and plated at 50,000 cells/well in complete growth media. After allowing cells to adhere, the media was removed and replaced with media containing 0.1% FBS and incubated overnight. Blank MSD plates (Mesoscale Discovery, Cat # L15XA3) were coated with 25 ⁇ /well RSK capture antibody (BD Biosciences, Cat. # 610226) and incubated at 4 °C overnight, then blocked with 150 ⁇ of 3% BSA solution.
  • the media from the cell culture plate was removed and replaced with 100 ⁇ of media containing a test compound and incubated for 120 minutes at 37 °C.
  • the media was removed and replaced with 55 ⁇ per well of lysis buffer with protease inhibitors (Roche Biosciences, Cat. # 11836170001) and phosphatase inhibitors (Sigma-Aldrich, Cat. # P-0044 and P-5726), followed by incubation at 4 °C for 30 minutes.
  • 50 ⁇ of lysate was transferred to a blocked MSD plate, followed by incubation at room temperature for 2 hours under constant shaking.
  • the plate was washed 3 times with MSD wash buffer (Mesoscale Discovery, Cat.
  • the protocol below describes an assay to measure the kinase activity of ER 1/2 to phosphorylate a substrate, p90RSK, in the presence or absence of a test compound.
  • A375 cells were grown in DMEM/10% FBS. Twenty four hours prior to the assay, 50,000 cells per well were plated in a 96 well flat bottom plate. Once cells attached to the plate, the medium was replaced with 100 ⁇ of DMEM/0.1% FBS. Cells were cultured overnight in an incubator at 37 °C.
  • MSD plates Blank MSD plates were coated with 30 ⁇ capture antibody (BD 610226) at a final concentration of 1 ⁇ g/mL in PBS. Both pRSK and total RSK MSD assays used the same capture antibody at the same concentration. Antibody stock concentration was 250 ⁇ g/mL. Once antibody solution was added to the MSD plate, the sides were tapped to be certain it was coated completely (visual inspection). It was then covered and placed at 4 °C overnight on a level surface.
  • capture antibody BD 6102266
  • Antibody stock concentration was 250 ⁇ g/mL.
  • Block MSD Plate The coating antibody was removed and the plate was washed on a plate washer in MSD wash buffer. The last bit of wash solution was tapped out and 150 ⁇ of 3% BSA in MSD wash buffer was added in. The preparation was placed on a shaker at room temperature for at least an hour.
  • pRSK detection a pRSK antibody stock of 21 ⁇ g/mL was prepared as follows: 1 ⁇ g/mL pRSK Ser380 antibody (Cell Signaling Technology, Cat. # 9335) + 1 :750 anti-rabbit SulfoTag (Mesoscale Discovery, Cat. # R32AB-1) in 1% BSA in MSD wash buffer.
  • a total RSK antibody stock of 200 ⁇ g/mL was prepared as follows: 1 ⁇ g/mL total RSK (Santa Cruz sc-231G) antibody + 1 :750 anti-goat SulfoTag (from MSD, R32AG-1) in 1% BSA in MSD wash buffer.
  • the protocol below describes an assay to measure the kinase activity of ERKl/2 to phosphorylate a substrate, p90RSK, in the presence or absence of a test compound.
  • HCT116 cells were grown in RPMI/10%FBS. Prior to the assay, 50,000 cells per well were plated in a 96 well flat bottom plate. Cells were cultured overnight in an incubator at 37 °C.
  • Compound stocks were 10 mM in DMSO. A lOOOx dilution was made in DMSO. 1 ⁇ _, of the DMSO solution was transfered to 1 ml RPMI/10%FBS in a deep well plate. Media in the cell plate was discarded, and 100 ⁇ , of the compound-containing media was added. The preparation was incubated at 37 °C for 2 hrs.
  • MSD plates Blank MSD plates were coated with 30 ⁇ . capture antibody (BD 610226) at a final concentration of 1 ⁇ g/mL in PBS. Both pRSK and total RSK MSD assays used the same capture antibody at the same concentration. Antibody stock concentration was 250 ⁇ g/mL. Once antibody solution was added to MSD plate, the sides were tapped to be certain it was coated completely (visual inspection). It was then covered and placed at 4 °C overnight on a level surface.
  • capture antibody BD 6102266
  • Both pRSK and total RSK MSD assays used the same capture antibody at the same concentration.
  • Antibody stock concentration was 250 ⁇ g/mL. Once antibody solution was added to MSD plate, the sides were tapped to be certain it was coated completely (visual inspection). It was then covered and placed at 4 °C overnight on a level surface.
  • Block MSD Plate The coating antibody was removed and the plate was washed on a plate washer in MSD wash buffer. The last bit of wash solution was tapped out and 150 ⁇ , ⁇ 3% BSA (MSD Blocker A) in MSD wash buffer was added. The preparation was placed on a shaker at room temperature for at least an hour.
  • MSD Blocker A MSD Blocker A
  • pRSK detection antibody For pRSK detection, a pRSK antibody stock of 21 ⁇ / ⁇ , was prepared as follows: 1 ⁇ /mL pRSK Ser380 antibody (Cell Signaling Technology, Cat. # 9335) + 1 :750 anti-rabbit SulfoTag (from MSD, R32AB-1) in 1% BSA in MSD wash buffer.
  • a total RSK antibody stock of 200 ⁇ g/mL was prepared as follows: 1 ⁇ g/mL total RSK (Santa Cruz sc-231G) antibody + 1 :750 anti-goat SulfoTag (from MSD, R32AG-1) in 1% BSA in MSD wash buffer.
  • Table A shows data for selected compounds in various assays.
  • Compound numbers in Table A correspond to Compound numbers indicated in the Tables and Examples above.
  • Compounds having an activity designated as "A” provided an EC 50 /IC 50 of 100-1000 nM; compounds having an activity designated as "B” provided an EC 50 /IC 50 of 1001-5000 nM; compounds having an activity designated as "C” provided an EC 50 /IC 50 of >5000 nM.

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiquement acceptables de ceux-ci, et des procédés d'utilisation de ceux-ci, dans l'inhibition d'une ou des deux ERK1 et ERK2.
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